Graduation Date
Spring 5-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Biochemistry & Molecular Biology
First Advisor
Chittibabu Guda
Abstract
The opioid crisis has emerged as one of the most pressing public health challenges of our time, with Opioid Use Disorder (OUD) affecting millions of lives across the globe. Studying OUD is not merely an academic pursuit but a critical necessity in addressing this multifaceted epidemic. The urgency of this research is underscored by the staggering prevalence of OUD, with an estimated 3.7% of U.S. adults requiring treatment in 2022 alone. Despite the availability of effective medications for OUD, a significant treatment gap persists, with only a quarter of those in need receiving these life-saving interventions. The far-reaching consequences of OUD extend beyond individual health, impacting economic stability and social dynamics. Moreover, the crisis has contributed to the spread of infectious diseases and placed immense strain on healthcare systems. By delving deeper into the study of OUD, researchers aim to enhance treatment effectiveness, address barriers to care, and develop innovative prevention strategies. This thesis seeks to explore the multifaceted nature of OUD, examining its genetics and epigenetic causes, and potential avenues for improvement in both prevention and intervention. Through a comprehensive analysis of existing literature and emerging research, this study aims to contribute to the body of knowledge necessary to combat the opioid crisis and ultimately save lives in the face of this ongoing public health emergency.
This study analyzes transcription factor (TF) binding dynamics, and genetic variants of OUD post- mortem patient brain particularly in Nucleus Accumbens (NAc) and putamen and how they affect the transcriptome which further contributes to changes in addiction neurocircuitry and behavior. The first part of the study revealed that differential binding dynamics in neurons and glia of heroin users in the putamen is associated with cell-type specific epigenetic modifications and chromatin remodeling. These changes could potentially alter gene expression programs crucial for synaptic plasticity and neural circuit adaptation, thereby contributing to the neuroadaptive processes underlying addiction. In the second part, our research identified unique exonic variants in the NAc of individuals with OUD, including missense and stop-gain mutations that could disrupt protein function and neural signaling. This segment also highlighted dysregulated gene expression and lncRNA-mediated networks affecting immune and cellular stress responses, further exacerbating maladaptive neuroplasticity. Together, these findings provide an integrated perspective on how both transcriptional regulation and genetic alterations drive the complex neuroplastic changes observed in substance use disorders (SUDs), offering new avenues for targeted therapeutic interventions.
Recommended Citation
Chakraborty, Rajashree, "Investigating the Effects of Transcription Factor Binding and Genetic Variants in the Striatum of Post-Mortem Cohorts with Opioid Use Disorder" (2025). Theses & Dissertations. 950.
https://digitalcommons.unmc.edu/etd/950
Comments
2025 Copyright, the authors